Meadiators of inflammation
• Mediators are the substances that
initiate and regulate inflammatory reactions.
• These are: cell derived or plasma protein derived
• vasoactive amines,
• lipid products,
• products of complement activation
• Active mediators are produced only in
response to various stimuli like microbial
• life span of mediators are very short
• one mediator can stimulate the release of
other like complement activation cause
release of histamine and cytokines
Vasoactive Amines: Histamine and
• Acts on blood vessels.
• First mediators
• Mast cells are richest source of histamine
• Histamine stored as granules and released by
degranulation in response to various stimuli
• 1. physical injuries
• 2.Antibodies mediated – hypersensitivity reaction
• 3. Complement products- anaphyltoxin C3a, C5a.
• 4. Neuropeptides (e.g., substance P) and cytokines
• Histamine causes dilation of arterioles and
increases the permeability of venules.
• principal mediator of the immediate transient
• it increased vascular permeability, producing
interendothelial gaps in venules.
• Act via H1 receptors present on microvascular
• preformed mediator
• Present in plateletes and certain
neuroendocrinal cells like GIT.
• primary function is as a neurotransmitter.
Arachidonic Acid Metabolites
• The lipid mediators prostaglandins and
leukotrienes are produced from arachidonic
acid (AA) present in membrane phospholipids
• Stimulate vascular and cellular reactions.
• Arachidonic acid derived from dietary sources
or by conversion from the linoleic acid.
• Mechanical, chemical, and physical stimuli or
other mediators (e.g., C5a) release AA from
membrane phospholipids through the action
of cellular phospholipases, mainly
• Phospholipase A2 Activation occur via
increase in cytosolic Ca2 + and kinase in
response to external stimuli.
• Produced by mast cells , macrophages,
endothelial cells, .
• it involved in vascular and systemic reactions of
• COX-1 & COX-2 is involved in synthesis of
• COX -1 is produced in response to inflammatory
stimuli and is also constitutively expressed
• COX2 is induced by inflammatory stimuli .
Thromboxane A2 (TxA2)
• derived by action of thromboxane synthase
present in platelets.
• Functions –
• platelets aggregation
• it is unstable and converted to inactive forms
• formed by action of prostacyclin synthase
present in vascular endothelium.
• increase vascular permeability
• inhibit platelets aggregation
• PGD2 produced by mast cells along with PGE2.
• it causes vasodilation and increases the
permeability of postcapillary venules, thus
potentiating edema formation.
• PGF2- stimulates contraction of uterine and
bronchial smooth muscles and small arterioles.
• Prostaglandins involved in the pathogenesis of
pain and fever in inflmmation.
• PGE2 is hyperalgesic makes the skin
hypersensitive to painful stimuli
• produced by leukocytes and mast cells by the
action of lipoxygenase.
• It involved in vascular and smooth muscle
reactions and leukocyte recruitment.
• Three types of lipoxygenase
1. - lipoxygenase – present in neutrophils, convert
AA to 5hydroxyeicosatetraenoic acid
• Act as chemotactic for neutrophils
• LTB4- Chemotactic and neutrophil activator.
• leads to aggregation and adhesion of the cells
to venular endothelium.
• Generation of ROS
• Release of lysosomal enzymes.
• LTC4, LTD4, and LTE4- causes
• increased permeability of venules
• Leukotrienes are more potent than is
histamine in increasing vascular permeability
and causing bronchospasm.
• Generated from AA by the lipoxygenase
• It suppress inflammation by inhibiting
recruitment of leukocytes.
• Inhibit neutrophil chemotaxis and adhesion to
Pharmacologic Inhibitors of Prostaglandins
• Cyclooxygenase inhibitors- aspirin and other
nonsteroidal anti-inflammatory drugs (NSAIDs)
• inhibit both COX-1 and COX-2
• COX1 is responsible for the production of
prostaglandins that are involved in both
inflammation and homeostatic functions (e.g.,
fluid and electrolyte balance in the kidneys,
cytoprotection in the gastrointestinal
• COX2 generates prostaglandins that are
involved only in inflammatory reactions.
• Lipoxygenase inhibitors- Zileuton
• Corticosteroids - broad spectrum anti-
• Reduce the transcription of genes encoding
COX2, phospholipase A2, proinflammatory
cytokines (e.g., IL1 and TNF), and iNOS
• Leukotriene receptor antagonists- block
receptor . eg Montelukast
Cytokines and Chemokines
• Cytokines are proteins produced by many cell
types (activated lymphocytes, macrophages,
and dendritic cells)
• mediate and regulate immune and
Tumor Necrosis Factor (TNF) and
• roles in leukocyte recruitment
• promoting adhesion of leukocytes to
endothelium and their migration through
• Produced by – macrophages and dendritic
• TNF also via T lymphocytes and mast
• Stimulus for secretion- microbial products,
immune complexes, foreign bodies, physical
injury, and a variety of other inflammatory
• TNF production is induced by TLRs and other
Roles of cytokines in inflammation
• Endothelial activation.- by TNF and IL-1
• increased expression of adhesion molecules ( P-
and E- selectins and ligands foe leukocytes
• increased production of various mediators
• increased procoagulant activity
• Activation of leukocytes and other cells-
• stimulates microbicidal activity of macrophages by
inducing production of NO.
• IL1 activates fibroblasts to synthesize collagen
and stimulates proliferation of synovial and other
• stimulates TH17 responses- induce acute
• Systemic acute-phase response
• Induced by IL-1, TNF and IL-6
• TNF regulates energy balance by promoting
lipid and protein mobilization and by
suppressing appetite leads to cachexia
• TNF antagonists have been remarkably
effective in the treatment of chronic
inflammatory diseases- Rheumatoid arthritis
• Chemokines are a family of small (8 to 10 kD)
proteins that act primarily as
chemoattractants for specific types
• About 40 different chemokines and 20
different receptors for chemokines have been
Classification of chemokines
• Four major groups
• 1. C-X-C chemokines- have one amino acid
residue separating the fist two of the four
conserved cysteine residues.
• Act primarily on neutrophils.
• Secreted by macrophages, endothelial cells
• function- Activation and chemotaxis of
• Eg. IL-8
• 2. C-C chemokines- have the fist two
conserved cysteine residues adjacent.
• It includes- monocyte chemoattractant
• macrophage inflmmatory protein1 α (MIP1 α),
• RANTES (regulated and normal Tcell expressed
• attract monocytes, eosinophils, basophils and
• eotaxin selectively recruits eosinophils.
• C chemokines -lack the first and third of the
four conserved cysteines.
• e.g., lymphotactin
• specific for lymphocytes.
• CX3C chemokines-contain three amino acids
between the two cysteines.
• eg- fractalkine exist in two forma
• cell surface bound protein- promotes strong
adhesion of monocytes and T cells,
• soluble form-derived
by proteolysis of the membrane bound
• potent chemo-attractant
• Chemokines mediate their activities by
binding to seven-trans membrane G protein–
• Functions of chemokines-
• In acute inflammation-stimulate leukocyte
attachment to endothelium by acting on
leukocytes to increase the affinity of integrins,
• Maintenance of tissue architecture
• homeostatic chemokines-produced
constitutively in tissues
Other Cytokines in Acute Inflammation
• IL- 6 – Secreted by macrophages involved in
local and systemic reactions
• IL-17 – Produced by T lymphocytes, promotes
• Type I interferons – some systemic
• The complement system is a collection of
soluble proteins and membrane receptors
that function mainly in host defense against
microbes and in pathologic inflammatory
• The system consists of more than 20 proteins,
some of which are numbered C1 through C9.
• functions in both innate and adaptive
The activation and functions of the
• Complement proteins are present in inactive
forms in the plasma.
• The critical step in complement
activation is the proteolysis of the third
• Cleavage of C3 can occur by one of
• classical pathway- triggered by fixation of
C1 to antibody (IgM or IgG) that has combined
• Alternative pathway- triggered by
microbial surface molecules (e.g., endotoxin,
or LPS), complex polysaccharides, cobra
venom, and other substances, in the absence
• The lectin pathway- plasma mannose binding
lectin binds to carbohydrates on microbes and
directly activates C1.
Functions of complements
• Inflammation- C3a, C5a and C4a
• stimulate histamine release
• They are called anaphylatoxins
• C5a – chemotactic to neutrophils, monocytes,
eosinophils, and basophils.
• Opsonization and phagocytosis- C3b and iC3b
• Cell lysis- deposition of the MAC on cells
makes these cells permeable to water and
ions and results in death (lysis) of the cells.
• The activation of complement is tightly
controlled by cell-associated and circulating
• C1 inhibitor (C1 INH)- block C1 activation
• Inherited deficiency of this inhibitor is the cause
of hereditary angioedema
• Decay accelerating factor (DAF) and CD59
• DAF- inhibit C3 convertase formation
• CD59 inhibits formation of the
membrane attack complex.
• An acquired deficiency leads to PNH.
Other Mediators of Inflammation
• Platelet-Activating Factor (PAF)- phospholipid
• Secreted by platelets, basophils, mast cells,
neutrophils, macrophages, and endothelial
• It causes- platelets aggregation
• at low concentrations it induces vasodilation
and increased venular permeability.
Products of Coagulation
• Kinins- vasoactive peptides derived from plasma
proteins, called kininogens, by the action of
specific proteases called kallikreins.
• Bradykinin- increases vascular permeability, and
smooth muscles contractions,
• Dilatation of blood vessels and pain
• Neuropeptides-secreted by sensory nerves and
• substance P and neurokinin A
• Substance P- prominent in nerve fibers in
lungs and GIT.
• Functions- transmission of pain signals
• regulation of blood pressure
• stimulation of hormone secretion by
• increasing vascular permeability.
Morphologic Patterns of Acute
• The morphologic hallmarks -dilation of small
• accumulation of leukocytes and fluid in the
• Various morphological pattern occur-
• Serous inflammation
• Fibrinous inflammation
• Purulent (Suppurative) Inflammation, Abscess
• Exudation of cell poor fluid into spaces
created by cell injury or into body cavities
lined by the peritoneum, pleura, or
• not infected by destructive organisms and
does not contain large numbers of leukocytes.
• accumulation of fluid in these cavities is called
• Eg. Skin blister in burn or viral infections
cross-section of a skin blister showing the epidermis
separated from the dermis by a focal collection of serous
• A fibrinous exudate develops when the
vascular leaks are large or there is a local
procoagulant stimulus (e.g., cancer cells)
• Fibrinous exudate is characteristic of
inflammation in the lining of body cavities,
such as the meninges, pericardium and pleura.
• Histologically, fibrin appears as an eosinophilic
meshwork of threads or sometimes as an
• Fibrinous exudates may be dissolved by
fibrinolysis and cleared by macrophages.
• If fibrin not removed it stimulates ingrowth of
fibroblast and blood vessels leads to scarring.
• Conversion of the fibrinous exudate
to scar tissue (organization) within the
pericardial sac leads to opaque fibrous
thickening of the pericardium and epicardium.
Fibrinous pericarditis. A, Deposits of fibrin on the
pericardium. B, A pink meshwork of fibrin exudate (F)
overlies the pericardial surface (P)
Purulent (Suppurative) Inflammation,
• characterized by the production
of pus, an exudate consisting of neutrophils,
the liquefied debris of necrotic cells, and
• Most common cause – bacterial infections
• Abscesses are localized collections of purulent
inflammatory tissue caused by suppuration
buried in a tissue, an organ, or a confined
• Abscesses have a central region that appears
as a mass of necrotic leukocytes and tissue
• zone of preserved neutrophils around this
necrotic focus, and outside this region there
may be vascular dilation and parenchymal and
Purulent inflammation. A, Multiple bacterial abscesses
(arrows) in the lung in a case of bronchopneumonia. B, The
abscess contains neutrophils and cellular debris, and is
surrounded by congested blood vessels.
• An ulcer is a local defect, or excavation, of the
surface of an organ or tissue that is produced
by the sloughing (shedding) of inflamed
• Most commonly encountered in
• the mucosa of the mouth, stomach, intestines,
or genitourinary tract
• skin and subcutaneous tissue of the lower
A chronic duodenal ulcer. B, Low-power cross-section view of a
duodenal ulcer crater with an acute inflammatory exudate in the